An essential role for the H218/AGR16/Edg‐5/LPB2 sphingosine 1‐phosphate receptor in neuronal excitability

A wealth of indirect data suggest that the H218/AGR16/Edg‐5/LPB2 sphingosine 1‐phosphate (S1P) receptor plays important roles in development. In vitro, it activates several forms of development‐related signal transduction and regulates cellular proliferation, differentiation and survival. It is expressed during embryogenesis, and mutation of an H218‐like gene in zebrafish leads to profound defects in embryonic development. Nevertheless, the in vivo functions served by H218 signalling have not been directly investigated. We report here that mice in which the H218 gene has been disrupted are unexpectedly born with no apparent anatomical or physiological defects. In addition, no abnormalities were observed in general neurological development, peripheral axon growth or brain structure. However, between 3 and 7 weeks of age, H218–/– mice have seizures which are spontaneous, sporadic and occasionally lethal. Electroencephalographic abnormalities were identified both during and between the seizures. At a cellular level, whole‐cell patch‐clamp recordings revealed that the loss of H218 leads to a large increase in the excitability of neocortical pyramidal neurons. Therefore, H218 plays an essential, unanticipated and functionally important role in the proper development and/or mediation of neuronal excitability.

[1]  A. MacLennan,et al.  Antisense Studies in PC12 Cells Suggest a Role for H218, a Sphingosine 1-Phosphate Receptor, in Growth-Factor-Induced Cell-Cell Interaction and Neurite Outgrowth , 2000, Developmental Neuroscience.

[2]  D. Stainier,et al.  A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development , 2000, Nature.

[3]  T. Bleu,et al.  Sphingosine 1-Phosphate-induced Cell Proliferation, Survival, and Related Signaling Events Mediated by G Protein-coupled Receptors Edg3 and Edg5* , 2000, The Journal of Biological Chemistry.

[4]  D. Im,et al.  Life on the edg. , 1999, Trends in pharmacological sciences.

[5]  W. Moolenaar.  Bioactive lysophospholipids and their G protein-coupled receptors. , 1999, Experimental cell research.

[6]  T. Ishizuka,et al.  Comparison of Intrinsic Activities of the Putative Sphingosine 1-Phosphate Receptor Subtypes to Regulate Several Signaling Pathways in Their cDNA-transfected Chinese Hamster Ovary Cells* , 1999, The Journal of Biological Chemistry.

[7]  S. Pyne,et al.  Extracellular actions of sphingosine I-phosphate through endothelial differentiation gene products in mammalian cells: role in regulating proliferation and apoptosis. , 1999, Biochemical Society transactions.

[8]  J. McNamara,et al.  Seizure disorders in mutant mice: Relevance to human epilepsies , 1999, Current Opinion in Neurobiology.

[9]  S. Wattler,et al.  Construction of Gene Targeting Vectors from λKOS Genomic Libraries , 1999 .

[10]  T. Bleu,et al.  Transduction of intracellular calcium signals through G protein-mediated activation of phospholipase C by recombinant sphingosine 1-phosphate receptors. , 1999, Molecular pharmacology.

[11]  S. Spiegel,et al.  Sphingosine 1-Phosphate-induced Cell Rounding and Neurite Retraction Are Mediated by the G Protein-coupled Receptor H218* , 1999, The Journal of Biological Chemistry.

[12]  J. Weiner,et al.  Comparative analysis of three murine G-protein coupled receptors activated by sphingosine-1-phosphate. , 1999, Gene.

[13]  S. Kimura,et al.  The novel sphingosine 1-phosphate receptor AGR16 is coupled via pertussis toxin-sensitive and -insensitive G-proteins to multiple signalling pathways. , 1999, The Biochemical journal.

[14]  E. Goetzl,et al.  Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1‐phosphate , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  E. Goetzl,et al.  Signaling mechanisms and molecular characteristics of G protein‐coupled receptors for lysophosphatidic acid and sphingosine 1‐phosphate , 1998, Journal of cellular biochemistry. Supplement.

[16]  A. MacLennan,et al.  Embryonic expression pattern of H218, a G-protein coupled receptor homolog, suggests roles in early mammalian nervous system development , 1997, Neuroscience.

[17]  E. Vinson,et al.  Immunohistochemical localization of ciliary neurotrophic factor receptor alpha expression in the rat nervous system , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  G. Shaw,et al.  Cloning and Characterization of a Putative G-Protein Coupled Receptor Potentially Involved in Development , 1994, Molecular and Cellular Neuroscience.

[19]  M. Rogawski,et al.  Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice , 1992, Epilepsy Research.

[20]  Sheryl M. Davies.  Surgery of Occlusive Cerebrovascular Disease , 1987, Neurology.